Recently, it has been proved that nitric oxide radical (hereinafter, occasionally abbreviated as .cndot.NO) is an active principle of endothelium-derived relaxing factor, and acts as an mediator for the signal transduction mechanism of neural cells. On the other hand, since .cndot.NO is an unstable radical, the overproduction and release thereof have been considered to damage various cells and tissues with the chemical hyper-reactivity thereof. Besides, it has been recently reported that .cndot.NO is an important factor in the pathogenesis of endotoxin-induced shock such as septic shock.
Koprowski, et al. reported that inducible nitric oxide synthase (iNOS) is induced in the brain tissue by Borna disease virus, rabies virus, herpes simplex virus, and NO is produced by cells induced by iNOS, which may be a toxic factor accounting for neural cell damages [Hilary Koprowski, et al., Proc. Natl., Acad. Sci. USA, 90, pp 3024-3027 (1993)]. It has been also reported that NMMA (N.sup.G -monomethyl-arginine), which is a nitric oxide synthase inhibitor, inhibits NO production which is induced by infection with Woodchuck hepatitis virus, and that formation of carcinogenic nitroso compounds could influence the induction of hepatocarcinogenesis [Cancer Res., 52 (15), 1992, pp 4139-4143]. Moreover, it has also been reported that L-NAME (N.sup.G -nitro-L-arginine methyl ester), another nitric oxide synthase inhibitor, inhibits the formation of prostaglandin E2 (PGE2) being induced by HIV coating glycoprotein (gp) 120, and that NO contributes to the involvement of neural cells in HIV-related cerebral disorders [Biochem. Biophys. Res. Commun., 203 (1), 1994, pp 87-92].
However, all these reports are concerned with physiological implications of .cndot.NO on neural cell damages or hepatocarcinogenesis, being induced by viral infection, but as to the direct action of .cndot.NO on virus per se, there has been reported antiviral activity of .cndot.NO dependent inhibition of virus replication, as mentioned below. That is, it has been reported in Science, 261 (5127), 1993, pp 1445-1448 that it is very important to induce NO synthase in order to demonstrate inhibitory effects on replication of ectromelia virus, vaccinia virus, herpes simplex virus, by activation of .gamma.-interferon. Besides, it has been also reported in J. Clin. Invest., 91 (6), 1993, pp 2446-2452 that .cndot.NO has inhibitory effects on protein and DNA synthesis of herpes simplex virus, i.e. .cndot.NO has an antiviral effect.
Until now, various inhibitors of .cndot.NO synthase (hereinafter, occasionally abbreviated as NOS) have been used in order to investigate the pathophysiological mechanism of .cndot.NO in the living body. Such NOS inhibitors include, for example, such substances inhibiting the induction or activation of NOS, substances inhibiting cofactors of NOS, and L-arginine analogues being competitive inhibitor for substrate of NOS. It is considered that these NOS inhibitors are useful not only for the analysis of the pathophysiological mechanism of .cndot.NO in the living body, but also can be possibly used in the treatment of cell and tissue damages, shock, ischemic diseases, etc.
Recently, the present inventors have found organic compounds rapidly reacting with .cndot.NO and strongly inhibiting physiological activities of .cndot.NO, i.e. imidazolinoxyl N-oxide derivatives (hereinafter, occasionally abbreviated as PTIO derivatives) as an .cndot.NO scavenger (Biochemistry, 32, 827-832, 1993). The PTIO derivatives are a stable organic radical species, and directly react with .cndot.NO, by which strongly inhibits the physiological activities of .cndot.NO.
There have been done various pharmacological tests on these effects of PTIO derivatives. For example, it has been reported that PTIO derivatives suppress vascular permeability caused by NO in a Sarcoma-180 solid cancer transplanted mouse (Jpn. J. Cancer Res. 85, 331-334, 1994); PTIO derivatives enhance an antibacterial activity of NO against Cryptococcus neoformans (Infect. Immun. 61, 3552-3555, 1993); PTIO derivatives show potent activities of maintaining blood pressure and of improving renal functions in a rat endotoxin shock model (Biochem. Biophys. Res. Commun., 202 (2), 1994, pp 923-930), etc. These reports all suggest the applicability of PTIO derivatives as an anticancer agent, an antibacterial agent, or an agent for treatment of shock, but there have never been reported as to effects of PTIO derivatives on viral infections.
Recently, it has been known in various viral infections that host immune response induced by viral infection disadvantageously affects the living body, and destroys host cells by immunological pathway, which is considered to be a diverse array of the pathogenesis mechanism. For example, in the pathogenesis in various inflammatory diseases, much attention has been focused on a role of an active oxygen, and it is reported that the level of oxygen radical (O.sub.2 .cndot.-) is increased greatly in the lung of mouse infected with influenza virus, and the increase thereof completely correlates with the development of severity of clinical signs. Moreover, O.sub.2 .cndot.- in the living body is eliminated by administering allopurinol, which is an inhibitor of xanthin oxidase (XOD) or polymer conjugated superoxide dismutase (SOD) with prolonged plasma half-life, into a virus infected mouse and as a result significant therapeutic effects are achieved. Based on these facts, it is indicated that some biofactors derived from the host such as oxygen radical may participate in the pathogenesis of viral infections.
However, there have been still many unclarified aspects of the role of biofactors in the pathogenesis during viral infections, and it has not been developed as an agent for treatment of viral infections which is highly useful in the view point of biofactors. Thus, an object of the present invention is to discover an agent for the treatment of viral infections by inhibiting viral pathogenesis.